A major effort in the laboratory is devoted to understanding dystonia. Our fundamental view is that there is a deficiency of inhibition in central nervous system mechanisms in dystonia. Specifically, an important type of defective inhibition is surround inhibition, where muscles and movements not desired for the task need to be inhibited. Lack of inhibition leads to motor overflow and action dystonia. We are trying to identify the specific inhibitory circuit that contributes to surround inhibition. Studies are first done in normal subjects and then in patients. We have investigated a variety of inhibitory mechanisms already, and we are now engaged in understanding the premotor to motor cortex interactions in focal hand dystonia. We are also exploring the physiology of motor learning in dystonia. Motor learning seems disturbed, and seems to have a principal role in producing focal hand dystonia since long term repetitive activity is certainly an etiological factor. In one type of experiment, we are evaluating brain and spinal cord plasticity using brain and nerve stimulation paradigms. We are also conducting a case-control experimental study to evaluate long-term learning of sequential finger movements in focal hand dystonia patients. We have been studying the mechanisms underlying the somesthetic discrimination deficit in focal hand dystonia using EEG. We are showing that the recovery function of cortical somatosensory evoked potential (SEP) component in the paired-pulse paradigm is impaired and that this was well correlated with somesthetic temporal discrimination capability. This suggests that there is a deficit in inhibition in sensory processing as well as motor processing. In order to study task specificity, we are engaged in some fMRI studies with various tasks and various limb effectors. We should hopefully identify which regions of brain are specific for a task, and then to see how this would malfunction in dystonia. Our first attempt with this will be to study handwriting and patients with writers cramp. To gather further evidence for abnormalities in dystonia we are also exploring evidence for anatomical changes and for a deficiency of GABA-ergic mechanism. We are doing MRI studies with voxel based morphometry (VBM), diffusion tensor imaging (DTI), GABA magnetic resonance spectroscopy (MRS), anatomical imaging at 7 tesla, flumazenil PET studies and pathological studies of brains of patients with focal dystonias. The genetic markers in focal dystonia are largely unknown. Currently, we are evaluating patients with all forms of focal dystonia (blepharospasm, cranial dystonia, cervical dystonia, focal hand dystonia and spasmodic dysphonia) to look for a genetic marker. The study involves large families with focal dystonia and individuals without a family history. We have collaborators in the NIA for the genetics work. We are also exploring further the physiology of Parkinson disease (PD). Although fatigue is one of the most common symptom in PD, its characteristics and etiology are largely unknown because it is a subjective, complicated symptom hard to evaluate. With objective measurement, we are planning to study the clinical features and the beneficial effect of levodopa and repetitive transcranial magnetic stimulation. We are initiating a project on the pathophysiology of gait freezing. The pathophysiology of medication-related compulsive behaviors (pathological gambling and hypersexuality) in PD is poorly understood. We are doing behavioral studies on the obsessive compulsive and impulse control symptoms in PD compared to normal subjects and other patients, such as focal hand dystonia. Additionally, we are doing neuroimaging studies in PD patients with and without these symptoms to look for abnormal brain patterns of activation. We are collaborating with investigators in NIA on the clinical aspects of patients with genetic forms of PD. In particular, we have a study of patients with the LRRK2 mutation (PARK8). We will be studying patients with overt disease, but also carriers of the mutation who may become symptomatic. This will show the earliest manifestations of disease and progression of signs and symptoms.